The role of interleukin-2, interleukin-12, and dendritic cells in cancer therapy.
OBJECTIVE
Recombinant interleukin-2 (rIL-2) administration can mediate regression of solid tumors in patients with melanoma and renal cell carcinoma. A better understanding of the mechanisms of rIL-2-mediated antitumor effects has led to the investigation of novel immunotherapeutic approaches. Two approaches that appear promising include administration of antigen-pulsed dendritic cells (DC) and administration of DC or genetically engineered fibroblasts expressing human interleukin-12 (IL-12). The rationale for these immunotherapeutic approaches and preliminary clinical studies are presented.


METHODS
We have conducted a pilot study to evaluate the feasibility of treating melanoma patients with peptide-pulsed DC. Six melanoma patients received 1 to 3 x 10(6) DC pulsed with synthetic melanoma antigenic peptides. The peptide-pulsed DC were infused weekly for 4 weeks. We have also treated 32 patients in a phase I/II trial with IL-12-producing fibroblasts. Patients received escalating doses of cells weekly for 4 weeks, which produced quantities of IL-12 ranging from 10 ng to 9 micrograms/24 hours.


RESULTS
Infusion of melanoma peptide-pulsed DC produced a complete response in one patient, and significant T-cell and DC infiltration of melanoma lesions was observed. Lesional and regional responses have been observed in patients with melanoma, head and neck carcinoma, and breast cancer who received intralesional injections of IL-12-producing fibroblasts. Phase II studies of this approach are planned and will be initiated in the next few months.


CONCLUSIONS
These studies confirm the feasibility of these novel immunotherapeutic approaches and demonstrate their potential antitumor activity. These approaches may be effective in patients with metastatic melanoma and other solid tumors, and they may ultimately be used to improve the efficacy of rIL-2-based immunotherapy.
Lotze
M T
MT
Department of Surgery, University of Pittsburgh Cancer Institute, PA 15261, USA.
Hellerstedt
B
B
Stolinski
L
L
Tueting
T
T
Wilson
C
C
Kinzler
D
D
Vu
H
H
Rubin
J T
JT
Storkus
W
W
Tahara
H
H
Elder
E
E
Whiteside
T
T
D002292:Carcinoma, Renal Cell / Q000628:therapy; D002465:Cell Movement / Q000187:drug effects; D003713:Dendritic Cells / Q000502:physiology* / Q000637:transplantation; D005240:Feasibility Studies; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000502:physiology*; D007376:Interleukin-2 / Q000502:physiology*; D008545:Melanoma / Q000628:therapy*; D008565:Membrane Proteins / Q000502:physiology; D010865:Pilot Projects
D007376:Interleukin-2; D008565:Membrane Proteins; C084881:flt3 ligand protein; D018664:Interleukin-12